The incidence of prostate cancer has steadily increased over the last decade, with an estimated one in every 5 men diagnosed with the disease and 1 man out of 33 dying from it. It has been noted in several studies that men who both smoke and take supplemental vitamin E have a significantly reduced incidence of prostate cancer development. The mechanism responsible for this unexpected synergy is not known. Our research suggests that a metabolite of vitamin E called tocopherylquinone might be mediating this effect via direct actions on prostate cancer cells. This metabolite has been shown to be present in high levels in rats given vitamin E and exposed to cigarette smoke, supporting the likelihood that it is also elevated in men who smoke and take vitamin E. Our data shows that tocopherylquinone, but not vitamin E, inhibits the growth of prostate cancer cells in culture and, importantly, that it decreases the expression of the receptor for androgen, a significant growth factor for prostate cells. The objectives of our current application are to both further understand the molecular mechanism by which tocopherylquinone decreases the expression of the androgen receptor and begin to assess whether tocopherylquinone will prevent prostate cancer development in mice genetically modified to develop prostate cancer. We will determine if the down-regulation of the androgen receptor is mediated by decreased production of the protein or by decreased stability of the protein after it is synthesized. Additionally, we will assess whether TQ treatment will delay or prevent the development of prostate cancer in a rodent prostate carcinogenesis model that is known to be dependent on androgen receptor activity for cancer development. The epidemiologic data are strongly supportive of a significant beneficial effect mediated by the combination of smoking with vitamin E intake which we believe is directly related to elevated tocopherylquinone levels in these individuals. The goal of this study is to link our observations in the laboratory with the epidemiologic data in order to establish tocopherylquinone as a potential dietary supplementation for prostate cancer prevention. We obviously do not intend to condone smoking as a health benefit because of the myriad of other health risks that are directly associated with it. Tocopherylquinone is a naturally occurring metabolite of vitamin E produced under certain physiological conditions (such as the oxidative stress produced in smokers), and therefore is likely to be well tolerated when administered directly. Moreover, by establishing a mechanism by which tocopherylquinone alters the expression level of the androgen receptor we can increase our overall understanding of the regulation and control of this important molecule which is a target for both prevention and therapy of prostate cancer. [unreadable] [unreadable] [unreadable] [unreadable]